Incipient damage identification through characteristics of the analytical signal response

The analytical signal is a complex representation of a time domain signal: the real part is the time domain signal itself, while the imaginary part is its Hilbert transform. It has been observed that damage, even at a very low level, yields clearly detectable variations of analytical signal quantities such as phase and instantaneous frequency. This observation can represent a step toward a quick and effective tool to recognize the presence of incipient damage where other frequency-based techniques fail. In this paper a damage identification procedure based on an adimensional functional of the square of the difference between the characteristics of the analytical theoretical and measured signal is proposed. Numerical examples, on a single degree of freedom system and of 3 degrees of freedom building model, prove the efficacy of the proposed method, its robustness in the presence of measuring errors, and show that the use of the signal phase leads to the best damage parameter estimation. Copyright © 2008 John Wiley & Sons, Ltd

Intrarenal hemodynamics and carotid intima-media thickness in the metabolic syndrome

Aims: Metabolic syndrome (MetS) is associated with increased cardiovascular risk. We hypothesize that early vascular changes are already present at the time of diagnosis of MetS. The relationship of different measures of early vascular impairment with body fat distribution and the natural progression of MetS was examined in newly diagnosed subjects non-pharmacologically treated. Methods: 246 consecutively enrolled subjects were categorized according to the presence of MetS and type 2 diabetes (T2D). Intra-renal Doppler flow was used to ascertain resistive (RI) and pulsatility (PI) indices as markers of vascular resistance. Carotid intima-media thick- ness (IMT), cutis-rectis (CR) and rectis-aorta (RA) thicknesses were measured by ultrasono- graphy; RA/CR ratio was used as measure of body fat distribution. Pro-inflammatory cytokines, C-reactive protein, oxidative markers insulin and adiponectin blood concentra- tions were also measured. Results: Baseline characteristics demonstrated increasing trends in biochemical, inflam- matory, and oxidative parameters from MetS??, MetS+, to MetS+/T2D (p<0.001). After adjusting for age, the same increasing trends across the groups were observed in both sexes in IMT (p < 0.001), RI (p < 0.001) and PI (p < 0.001). IMT correlated with RI (r = 0.25; p < 0.001), PI (r = 0.26; p < 0.001), and RA/CR ratio (r = 0.43; p < 0.001). Conclusions: Carotid IMT and intra-renal resistances are elevated at an early stage in MetS and are associated with a dysregulated production of fat-derived hormones and cytokines

Off-Adherence Keeping (OAK) observational study: intentional off-adherence immunomodulatory multiple sclerosis treatment

Aims: To evaluate how improved treatment adherence with a lower-frequency regimen/treatment of intramuscular (IM) IFN beta-1a impacts therapeutic effectiveness in relapsing-remitting multiple sclerosis (MS) patients switching from a higher-frequency injectable regimen/treatment. Patients & methods: Italian patients with relapsing-remitting MS and prior poor adherence to high-frequency injectable treatments (n = 181) were followed for 24 months after starting IM IFN beta-1a. Results: During the study, 97.4% of patients were treatment adherent; 22.1% of patients reported a relapse. The estimated probability of remaining relapse-free after 2 years was 78%. A high dropout rate (52.5%) led to small sample size and reduced statistical power. Conclusion: Intramuscular IFN beta-1a treatment was associated with high adherence and a low relapse rate. Unfortunately, low patient retention limited the generalizability of these findings.Plain language summary: Prior research suggests that taking the drug IFN beta-1a through less frequent muscle injections enables more patients to adhere to their prescription than taking other medications. This study included 181 Italian patients with relapsing-remitting multiple sclerosis (MS) who historically did not take medication as often as prescribed. Relapses of MS were counted among patients treated with muscle injections of IFN beta-1a for 2 years; 97.4% of patients followed their prescription and 22.1% experienced a relapse. From these data, 78% of patients were estimated not to experience a relapse during 2 years of IFN beta-1a muscle injections. However, an unusually high number of patients (52.5%) left the study within 2 years, which makes it difficult to draw firm conclusions

Short and middle term effects of hypocaloric low carbohydrate diet vs hypocaloric Mediterranean diet on endothelial function in obese subjects

Adequate nutritional treatment is required to address the problem of increasing prevalence of obesity in Western countries. The Mediterranean diet style is now acknowledged to have large scientific evidences in terms of cardiovascular prevention. However, many popular diets are diffusing also as self-prescribed treatments. Among those, the efficacy of low-carbohydrate diets (also known as Atkins’ diet in its most popular variety) has been addressed by some investigations. It is generally concluded that the low-carbohydrate diet is able to induce a greater weight loss, at least in the middle term, and a better serum lipid profile than the conventional diet. In this longitudinal, randomised, open study we compared the effects on endothelial function of a hypocaloric low-carbohydrate diet (according to the Atkins’ diet; AD) versus a similarly hypocaloric Mediterranean diet (MD). Overweight-obese (range of BMI: 27-34.9 Kg/m2; range of age: 30-50 years) otherwise healthy, normal glucose tolerant women were enrolled and randomly assigned to one of the two dietary treatments until reaching the final number of 10 women for each group of treatment. So, twenty-five women were enrolled and five of them (3 in the MD group and 2 in the AD group) were subsequently excluded from the study due to intercurrent diseases (1 subject) or declaration of inadequate compliance (2 subjects) or f voluntary drop out (2 subjects). Measurements were performed before (T0), 5-7 days (T5) and 2 months (T60) after starting the diet treatment. Endothelial function was investigated at each time of the study by measuring the brachial artery flow-mediated dilation (FMD). Serum concentrations of insulin, adiponectin, interleukin 6 (IL-6), tumor necrosis factor α (TNF-α) and 8-iso-prostaglandin (8-iso-PG) F2α were also assessed at each time of the study. Urinary ketone bodies were observed at T5 only in AD group. Briefly, body weight was not significantly decreased at T5 in both groups; as expected, a higher body weight reduction was observed at T60 in AD group (change in body weight T60 – T0, mean ± sem, MD -4.9 ± 0.6 Kg vs AD -7.6 ± 0.8 Kg, p= 0.014). The FMD was significantly reduced at T5 in the AD group and increased at T60 until reaching the T0 values (T0: 12.2 ± 2.9; T5: 5.2 ± 0.8; T60: 11.0 ± 1.2 %; p< 0.05 T5 vs T0 and T60). On the contrary, the FMD increased significantly at T5 in the MD group and decreased until reaching values comparable to those of T0 at T60 (T0: 10.3 ± 2.3; T5: 14.5 ± 2.8; T60: 10.6 ± 1.9 %; p< 0.05 T5 vs T0 and T60). This trend of FMD change was observed in each subject. Insulin concentrations and HOMA-I decreased significantly at T5 and at T60 in both groups. Adiponectin and TNF-α concentrations remained unchanged in both groups throughout the study. Both IL-6 and 8-iso-PGF2α increased significantly at T5 in the AD group and decreased at T60 to values comparable to T0 (IL-6: T0 57.5 ± 9.0, T5 78.1 ± 10.9, T60 56.6 ± 6.8 pg/ml; T5 vs T0 p< 0,005, T5 vs T60 p< 0,02; 8-iso-PGF2α: T0 171.5 ± 30.6, T5 222.6 ± 35.1, T60 178.7 ± 25.8 pg/ml; T5 vs T0 p< 0,005, T5 vs T60 p< 0,02); no significant change was observed in the MD group. This study suggests that the hypocaloric low-carbohydrate diet induces a significant endothelial dysfunction in the short term (5-7 days) that is reverted in the middle term (2 months) as suggested by both the brachial artery FMD and serum markers of inflammation (IL-6) and oxidative stress (8-iso-PGF2α). On the contrary, the hypocaloric Mediterranean diet is able to improve the endothelial function at least in the short term. These effects are independent of body weight loss. Therefore, this study points out also the potential disadvantages of low-carbohydrate diets when prescribed (or self-prescribed) especially in subjects at high cardiovascular risk

VALIDATION OF A MODIFIED MODEL OF TNBS-INDUCED COLITIS IN RATS. HOW TO INDUCE A CHEMICAL COLITIS IN RATS.

Background: there are no standard practice in the induction of colitis by 2,4,6-trinitrobenzene sulfonic (TNBS) acid. Usually, the repeated administration of TNBS is preferred, because it will result in a local Th1 response that has the characteristics of Crohn's disease. material and Methods: A total of 30 rats were randomized into two groups, consisting of a saline control group of ten rats and a TNBS groups of 20 rats. After the animals were anesthesized, 0,5 ml of either 0,9 % saline 8controls) or TNBS 50 mg/Kg dissolved in 50% ethanol were instilled into the colon through a rubber catheter. The experiment was repeated weekly for four weeks, then, the rats were killed at day 40, and the distal colon removed. results: At day 40, the bowel wall basically normal in the control group. In the TNBS group, the bowel lumen became narrow with tickened wall, and the mucosal surface presented adherent membrane with brown black, linear ulcers, proliferous lymphocites tissue, inflammatory granulomas and submucosal neutrophil infiltration. The median score of the severity of the colonic damage was 0 in the control group, and 4,75 (range 4-5) in the TNBS group; the mean weight of the rats was 180+35 g in the TNBS group, while it was 215+25 in the control group. Conclusions: The presented experiment is a cost-effective and safe method to induce Crohn-like colonic damage using a lower dose of TNBS, thus avoiding the risk of a massive loss of rats. This model is rather suitable for the assessment of the effects of potential therapeutic agent

Effect of natalizumab on disease progression in secondary progressive multiple sclerosis (ASCEND). a phase 3, randomised, double-blind, placebo-controlled trial with an open-label extension

Background: Although several disease-modifying treatments are available for relapsing multiple sclerosis, treatment effects have been more modest in progressive multiple sclerosis and have been observed particularly in actively relapsing subgroups or those with lesion activity on imaging. We sought to assess whether natalizumab slows disease progression in secondary progressive multiple sclerosis, independent of relapses. Methods: ASCEND was a phase 3, randomised, double-blind, placebo-controlled trial (part 1) with an optional 2 year open-label extension (part 2). Enrolled patients aged 18–58 years were natalizumab-naive and had secondary progressive multiple sclerosis for 2 years or more, disability progression unrelated to relapses in the previous year, and Expanded Disability Status Scale (EDSS) scores of 3·0–6·5. In part 1, patients from 163 sites in 17 countries were randomly assigned (1:1) to receive 300 mg intravenous natalizumab or placebo every 4 weeks for 2 years. Patients were stratified by site and by EDSS score (3·0–5·5 vs 6·0–6·5). Patients completing part 1 could enrol in part 2, in which all patients received natalizumab every 4 weeks until the end of the study. Throughout both parts, patients and staff were masked to the treatment received in part 1. The primary outcome in part 1 was the proportion of patients with sustained disability progression, assessed by one or more of three measures: the EDSS, Timed 25-Foot Walk (T25FW), and 9-Hole Peg Test (9HPT). The primary outcome in part 2 was the incidence of adverse events and serious adverse events. Efficacy and safety analyses were done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01416181. Findings: Between Sept 13, 2011, and July 16, 2015, 889 patients were randomly assigned (n=440 to the natalizumab group, n=449 to the placebo group). In part 1, 195 (44%) of 439 natalizumab-treated patients and 214 (48%) of 448 placebo-treated patients had confirmed disability progression (odds ratio [OR] 0·86; 95% CI 0·66–1·13; p=0·287). No treatment effect was observed on the EDSS (OR 1·06, 95% CI 0·74–1·53; nominal p=0·753) or the T25FW (0·98, 0·74–1·30; nominal p=0·914) components of the primary outcome. However, natalizumab treatment reduced 9HPT progression (OR 0·56, 95% CI 0·40–0·80; nominal p=0·001). In part 1, 100 (22%) placebo-treated and 90 (20%) natalizumab-treated patients had serious adverse events. In part 2, 291 natalizumab-continuing patients and 274 natalizumab-naive patients received natalizumab (median follow-up 160 weeks [range 108–221]). Serious adverse events occurred in 39 (13%) patients continuing natalizumab and in 24 (9%) patients initiating natalizumab. Two deaths occurred in part 1, neither of which was considered related to study treatment. No progressive multifocal leukoencephalopathy occurred. Interpretation: Natalizumab treatment for secondary progressive multiple sclerosis did not reduce progression on the primary multicomponent disability endpoint in part 1, but it did reduce progression on its upper-limb component. Longer-term trials are needed to assess whether treatment of secondary progressive multiple sclerosis might produce benefits on additional disability components. Funding: Biogen

Patient adherence to and tolerability of self-administered interferon β-1a using an electronic autoinjection device: a multicentre, open-label, phase IV study

<p>Abstract</p> <p>Background</p> <p>Achieving good adherence to self-injected treatments for multiple sclerosis can be difficult. Injection devices may help to overcome some of the injection-related barriers to adherence that can be experienced by patients. We sought to assess short-term adherence to, and tolerability of, interferon (IFN) β-1a administered via electronic autoinjection device in patients with relapsing-remitting multiple sclerosis (RRMS).</p> <p>Methods</p> <p>BRIDGE (RebiSmart to self-inject Rebif serum-free formulation in a multidose cartridge) was a 12-week, multicentre, open-label, single-arm, observational, Phase IV study in which patients self-administered IFN β-1a (titrated to 44 μg), subcutaneously (sc), three times weekly, via electronic autoinjection device. Patients were assessed at baseline and 4-weekly intervals to Week 12 or early termination (ET) for: physical examinations; diary card completion (baseline, Weeks 4, 8 only); neurological examinations (baseline, Week 12/ET only); MS Treatment Concern Questionnaire (MSTCQ; Weeks 4, 8, 12 only); Convenience Questionnaire (Week 12 only); Hospital Anxiety and Depression Scale (HADS); and Paced Auditory Serial Addition Task (PASAT; baseline only). Adherence was defined as administration of ≥ 80% of scheduled injections, recorded by the autoinjection device.</p> <p>Results</p> <p>Overall, 88.2% (105/119; intent-to-treat population) of patients were adherent; 67.2% (80/119) administered all scheduled injections. Medical reasons accounted for 35.6% (31/87) of missed injections, forgetfulness for 20.6% (18/87). Adherence did not correlate with baseline Expanded Disability Status Scale (<it>P </it>= 0.821) or PASAT (<it>P </it>= 0.952) scores, or pre-study therapy (<it>P </it>= 0.303). No significant changes (baseline-Week 12) in mean HADS depression (<it>P </it>= 0.482) or anxiety (<it>P </it>= 0.156) scores were observed. 'Overall convenience' was the most important reported benefit of the autoinjection device. Device features associated with handling and ease of use were highly rated. Mean MSTCQ scores for 'flu-like' symptoms (<it>P </it>= 0.022) and global side effects (<it>P </it>= 0.002) significantly improved from Week 4-12. Mean MSTCQ scores for pain at injection site and injection pain increased from Week 4-12 (<it>P </it>< 0.001). Adverse events were mild/moderate. No new safety signals were identified.</p> <p>Conclusion</p> <p>Convenience and ease of use of the autoinjection device may improve adherence and, therefore, outcomes, in patients with RRMS receiving sc IFN β-1a.</p> <p>Trial registration</p> <p>EU Clinical Trials Register (EU-CTR; <url>http://www.clinicaltrialsregister.eu</url>): 2009-013333-24</p

Disease-Modifying Therapies and Coronavirus Disease 2019 Severity in Multiple Sclerosis

Objective: This study was undertaken to assess the impact of immunosuppressive and immunomodulatory therapies on the severity of coronavirus disease 2019 (COVID-19) in people with multiple sclerosis (PwMS). Methods: We retrospectively collected data of PwMS with suspected or confirmed COVID-19. All the patients had complete follow-up to death or recovery. Severe COVID-19 was defined by a 3-level variable: mild disease not requiring hospitalization versus pneumonia or hospitalization versus intensive care unit (ICU) admission or death. We evaluated baseline characteristics and MS therapies associated with severe COVID-19 by multivariate and propensity score (PS)-weighted ordinal logistic models. Sensitivity analyses were run to confirm the results. Results: Of 844 PwMS with suspected (n = 565) or confirmed (n = 279) COVID-19, 13 (1.54%) died; 11 of them were in a progressive MS phase, and 8 were without any therapy. Thirty-eight (4.5%) were admitted to an ICU; 99 (11.7%) had radiologically documented pneumonia; 96 (11.4%) were hospitalized. After adjusting for region, age, sex, progressive MS course, Expanded Disability Status Scale, disease duration, body mass index, comorbidities, and recent methylprednisolone use, therapy with an anti-CD20 agent (ocrelizumab or rituximab) was significantly associated (odds ratio [OR] = 2.37, 95% confidence interval [CI] = 1.18-4.74, p = 0.015) with increased risk of severe COVID-19. Recent use (&lt;1 month) of methylprednisolone was also associated with a worse outcome (OR = 5.24, 95% CI = 2.20-12.53, p = 0.001). Results were confirmed by the PS-weighted analysis and by all the sensitivity analyses. Interpretation: This study showed an acceptable level of safety of therapies with a broad array of mechanisms of action. However, some specific elements of risk emerged. These will need to be considered while the COVID-19 pandemic persists

COVID-19 Severity in Multiple Sclerosis: Putting Data Into Context

Background and objectives: It is unclear how multiple sclerosis (MS) affects the severity of COVID-19. The aim of this study is to compare COVID-19-related outcomes collected in an Italian cohort of patients with MS with the outcomes expected in the age- and sex-matched Italian population. Methods: Hospitalization, intensive care unit (ICU) admission, and death after COVID-19 diagnosis of 1,362 patients with MS were compared with the age- and sex-matched Italian population in a retrospective observational case-cohort study with population-based control. The observed vs the expected events were compared in the whole MS cohort and in different subgroups (higher risk: Expanded Disability Status Scale [EDSS] score &gt; 3 or at least 1 comorbidity, lower risk: EDSS score ≤ 3 and no comorbidities) by the χ2 test, and the risk excess was quantified by risk ratios (RRs). Results: The risk of severe events was about twice the risk in the age- and sex-matched Italian population: RR = 2.12 for hospitalization (p &lt; 0.001), RR = 2.19 for ICU admission (p &lt; 0.001), and RR = 2.43 for death (p &lt; 0.001). The excess of risk was confined to the higher-risk group (n = 553). In lower-risk patients (n = 809), the rate of events was close to that of the Italian age- and sex-matched population (RR = 1.12 for hospitalization, RR = 1.52 for ICU admission, and RR = 1.19 for death). In the lower-risk group, an increased hospitalization risk was detected in patients on anti-CD20 (RR = 3.03, p = 0.005), whereas a decrease was detected in patients on interferon (0 observed vs 4 expected events, p = 0.04). Discussion: Overall, the MS cohort had a risk of severe events that is twice the risk than the age- and sex-matched Italian population. This excess of risk is mainly explained by the EDSS score and comorbidities, whereas a residual increase of hospitalization risk was observed in patients on anti-CD20 therapies and a decrease in people on interferon